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McKechnie was born in 1942 in Pontiac, Michigan, the daughter of James McKechnie and Murel Vera Stevenson, immigrants from Scotland and Canada respectively. She began ballet classes at age five. Her earliest influence was the classic Britishballet film The Red Shoes (1948), which prompted her, at age eight, to plan a career as a ballerina. She studied for many years at the Rose Marie Floyd School of Dance in Royal Oak. Despite her parents' strong misgivings, she moved to New York City when she was 17. Rejected after an audition for the American Ballet Theatre, she found employment in the corps de ballet at Radio City Music Hall but walked off the job on the day of dress rehearsal to do summer stock at the Carousel Theatre in Framingham, Massachusetts.

She also appeared as Philia in the national tour of "Forum," starring Jerry Lester (Pseudolus), with Paul Hartman (Senex), Erik Rhodes (Marcus Lycus), Arnold Stang (Hysterium) and Edward Everett Horton (Erronius), produced by Martin Tahse.

McKechnie was part of Bennett's group therapy-style workshops that evolved into the Broadway smash A Chorus Line, in which she portrayed Cassie, a character based in great part on herself. She danced her third famous Bennett-McKechnie number, The Music and the Mirror, in which the vocal sections were tailored to her unusually large range. Initially, Donna was to perform the number with four of her male co-stars but after four previews before opening, McKechnie voiced concern about dancing around the four guys and at the last moment, Bennett changed the direction to have McKechnie perform the song-dance number alone. Her performance earned her the Tony Award for Best Actress in a Musical. The role of Maggie was also based on her life. She married Bennett in 1976, but after only a few months they separated and eventually divorced, remaining good friends until his death from AIDS in 1987.

In 1980, McKechnie was diagnosed with arthritis and told she never would dance again. She went on to choreograph NFL's Football's Fabulous Females, The Los Angeles Raiderettes in 1983 as they made their debut in L.A. She pursued various physical, psychological, and holistic healing remedies, and was well enough to return to the Broadway company of A Chorus Line in 1986. During the remainder of the 1980s she also toured in Sweet Charity and Annie Get Your Gun, and she appeared in a London revival of Can-Can. She also participated in the "Chorus Line" extravaganza to celebrate its then record-breaking run on Broadway in September 1983.

Her television work included a regular role on the Gothic soap opera, Dark Shadows early in her career, and after her rise to fame, guest appearances on Scarecrow and Mrs. King, Rowan & Martin's Laugh In and Cheers as Deborah, the ex-wife of Sam Malone, plus the role of Suzi Laird on several Fame episodes.

In 2002, McKechnie starred in the pre-Broadway production of the Jerry Herman musical revue Showtune. In recent years, she has toured periodically in her one-woman show Inside the Music, a potpourri of songs, dances and anecdotes about her life in the theater and her successful battle with arthritis, directed by her old Chorus Line castmate, Thommie Walsh. Her autobiography, Time Steps: My Musical Comedy Life, written with Greg Lawrence, was published by Simon & Schuster on August 29, 2006, only weeks before the Broadway revival of A Chorus Line opened on October 5.

In June 2010 McKechnie appeared at the Adelaide Cabaret Festival.

McKechnie currently is on the faculty of HB Studio in New York City. She also is currently serving as the standby for Chita Rivera in Kander & Ebb'sThe Visit on Broadway.